Anxiety disorders are the most common form of mental disorders in the United States, affecting nearly 40 million American adults and more efficacious pharmacological treatments are needed. This project, to be conducted at Boston University in the rich neuroscience community of Boston, concerns the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP), a member of the secretin/glucagon/VIP superfamily, and a pleiotropic molecule with remarkable central actions on neuroendocrine and behavioral systems. Although the interest towards this fascinating polypeptide continues to increase exponentially, the role of this neuropeptide in the modulation of stress response and its function in the extended amygdala, a key brain site for the behavioral manifestations of stress, are yet to be elucidated. Continued existence of this gap represents an obstacle to the potential benefits that can derive by understanding the role of PACAP in stress and anxiety disorders. Our preliminary data suggest a role for PACAP in the modulation of behavioral response to stress, which seems to be mediated by the receptors of the major brain stress peptide, corticotropin-releasing factor (CRF). Our long-term goal is therefore to elucidate the role of neuropeptide systems in the neurobiology of stress- related disorders. The objective of this application is to understand how the PACAP system is involved in the behavioral response to stress, with the long-term goal to provide novel therapeutic strategies for the management of stress and anxiety disorders. The central hypothesis under test in this proposal is that the endogenous PACAP system in the extended amygdala is recruited following exposure to stress and that PAC1 receptor antagonists exert an anxiolytic-like action. A sub-hypothesis is that the anxiogenic effects of PACAP are mediated by the recruitment of the extra-hypothalamic CRF system. This hypothesis will be tested by pursuing three specific aims; the brain sites important for the anxiogenic effects of PACAP will be characterized in Specific Aim 1, using intracranial microinjection of PACAP-38. The role of endogenous brain PACAP system in anxiety-like behavior will be explored in Specific Aim 2, through the investigation of the potential anxiolytic effect of a PAC1 antagonist and of the effects of stressors on PACAP and PAC1 receptor levels in discrete brain regions. Finally Specific Aim 3 will investigate the role of hypothalamic and extrahypothalamic CRF in the effects of PACAP using a pharmacological and molecular approach. The results of the proposed experiments, through this multidisciplinary approach, will provide novel insights into this neuropeptide system as a mechanism for modulating anxiety-like behavior, and may ultimately lead to the a new class of therapeutic agents for the treatment of anxiety-like disorders. PUBLIC HEALTH RELEVANCE: The results of the present studies, providing key information regarding the role of the neuropeptide PACAP in stress and anxiety, will define specific mechanisms underlying anxiety disorders, and may provide novel therapeutic strategies for stress-related disorders and anxiety.